Sustained release dosage form

ABSTRACT

The novel sustained release dosage form comprising an active agent and a combination of a non-swelling pH dependent release retardant and a non swelling pH independent release retardant polymer which provides pH-independent drug release for a considerable period of time after administration.

FIELD OF INVENTION

The present invention relates to a novel sustained release dosage formof an active agent comprising a combination of a non-swelling pHdependent release retardant and a non swelling pH independent releaseretardant and providing pH-independent drug release for a considerableperiod of time after administration.

The present invention particularly relates to active agents havingsolubility of greater than 1 mg/ml.

BACKGROUND OF INVENTION

The advantages of sustained release formulations are well known in thepharmaceutical field. These include the ability of the givenpharmaceutical preparation to maintain a desired therapeutic effect overa comparatively longer period of time, reduced side effects, etc.Moreover, for drugs having a short elimination half-life, less frequentadministration and better patient compliance may be obtained withsustained release preparations as compared to the conventional dosageforms.

Development of a sustained release dosage form demands considerableunderstanding of the gastrointestinal physiology. There is a natural pHgradient down the gut from acidity of stomach to weakly acidic duodenumto the neutral environment of the small intestine. Also there arepossible fluctuations in pH arising from dietary changes.

Another important factor is the transit time of the dosage form. Transittime determines the time period for which a dosage form remains in aparticular segment of gastrointestinal tract. The transit time usuallydepends on the dosage form itself, gastric motility, presence of foodetc.

Combination of pH and transit time determines the environmentexperienced by a dosage form for example transit time of a tablet instomach under fasting condition may range from 0.5-2 hours. This meansthat a tablet will experience a pH of less than 2 for a period of 0.5-2hours.

These factors, i.e. transit time and pH are highly variable fordifferent individuals, same individual at different time periods, andtherefore these factors become very crucial for release of active agentparticularly from a modified release dosage form. It is always desirablefor optimal use of the drug product that the product be independent ofthese variabilities and avoid the associated problems of bioavailabilityvariation.

Prior art discloses many patents on controlled and sustained releasedelivery systems, some of which also describes formulations giving pHindependent release profiles.

U.S. Pat. Nos. 4,927,640, 4,957,745 and 5,246,714 describe controlledrelease beads comprising a compact inert core, which is insoluble and apolymeric membrane. The inner core is made of silicon dioxide, glass orplastic resin particles while the polymeric membrane covering thepharmaceutically active compound may be ethyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylphthalate, cellulose acetate phthalate, Eudragit RL or Eudragit RS.Although such systems provide pH independent release profile, theprocess of manufacturing is very complicated and involves use of organicsolvents, which is not desirable. The complicated manufacturing stepsmake the process cumbersome, time consuming and expensive.

U.S. Pat. No. 4,792,452 discloses controlled release pharmaceuticalcompositions, which provide pH-independent release for a basic drug. Theformulations include a pH-dependent polymer, which is a salt of alginicacid, a pH-independent hydrocolloid gelling agent and a binder and theformulation is free of calcium ion and carbon dioxide-producingmaterial. The salt of the alginic acid is preferably sodium alginate orpotassium alginate. This patent is applicable only for basic drugs andcannot be applied to acidic or neutral drugs. Moreover the system isdependent on highly variable physiological conditions for conversion ofsodium alginate to alginic acid and back to sodium alginate. This mayresult in inter patient as well as intra patient variabilities leadingto suboptimal product performance.

WO02058676 describes a composition exhibiting a pH independent releaseprofile of an active having pH dependent solubility. The formulationcomprises a combination of pH independent and a pH dependent polymerwhich increases dissolution rate of active at a pH greater than 5.5.

WO0045793 discloses extended release formulations of acidic drugs, whichhave reduced dependence of release rate on pH. The dosage form includesa neutral water swellable hydrophilic polymer and acid soluble polymer,which is water swellable above pH 5.0.

U.S. Pat. No. 6,346,268 discloses a controlled release formulationcomprising a pH dependent gelling polymer, an enteric polymer and a pHindependent gelling polymer.

The last three patents, mentioned above, describe formulations of drugshaving pH dependent solubilities, which tend to make the release of drugalso pH dependent. These patents therefore employ a pH dependent polymerto increase the dissolution of the drug in a medium, where itssolubility is low, so as to achieve constant drug release. These patentsalso disclose use of a pH independent, swelling release-retardingpolymer, which control the release of the active agent. These systemshowever may not be useful for drug molecules having high aqueoussolubility, which is independent of the pH of the medium. Use of thesesystems may result in undesirably high initial burst release of thedrug.

Thus there is a need to develop a sustained release dosage form, whichperforms reproducibly with low variability. Such dosage forms would havetwo essential features—(1) pH independent drug release for aconsiderable period of time and, (2) absence of significant swelling ofthe dosage form leading to predictable gastrointestinal transit profile.

It was surprisingly found that both these desired features were achievedby the dosage form of the present invention by employing a combinationof a non-swelling pH dependent release retardant and a non-swelling pHindependent release retardant. It is generally known in the art that useof pH dependent release retardants alone results in a release profile ofthe active ingredient, which is dependent on the pH of the environment.However optimal selection of type and concentration of releaseretardants by the present inventors has resulted in a sustained releasedosage form, which releases drug at a rate that is independent of thesurrounding milieu for a considerable period of time.

OBJECT OF INVENTION

It is an object of the present invention to provide oral sustainedrelease dosage forms of pharmaceutically active agents comprising acombination of non-swelling pH dependent release retardant andnon-swelling pH independent release retardant.

It is a further object of the present invention to provide an oralsustained release dosage form for drugs having aqueous solubility of atleast 1 mg/ml.

It is another object of the invention to provide a pH independent drugrelease profile for a considerable period of time after administrationof the dosage form.

Yet another object of the present invention is to provide a method forpreparation of sustained release dosage form, wherein the non-swellingpH dependent release retardant and the non-swelling pH independentrelease retardant are added intragranularly or extragranularly or bothsuch that pH independent drug release is obtained for a considerableperiod of time after administration.

Yet another further object of the present invention is to provide anoral sustained release dosage form.

SUMMARY OF INVENTION

According to a broad aspect of the present invention there is providedan oral sustained release dosage form comprising,

-   -   (i) therapeutically effective amount of pharmacologically active        ingredient having aqueous solubility of greater than 1 mg/ml,    -   (ii) at least one non-swelling pH dependent, release retardant,        and    -   (iii) at least one non-swelling pH independent,        release-retardant,        wherein the said dosage form provides pH independent drug        release for a considerable period of time after administration.

BRIEF DESCRIPTION OF FIGURES

FIG. 1: In vitro release of composition 1 in pH 6.8 phosphate buffer.

FIG. 2: In vitro release of composition 1 in different media.

FIG. 3: Comparative in vitro release profile of composition 2,composition 3 and composition 1 with marketed formulation.

FIG. 4: Comparative in vitro release profile of composition 4 indifferent media

FIG. 5: Comparative in vitro release profile of composition 5 withmarketed formulation.

DESCRIPTION OF INVENTION

The present inventors have addressed the need of developing a sustainedrelease dosage form providing pH independent drug release profile. Itwas surprisingly found that the much desired pH independent drug releasewas achieved using a combination of pH dependent release retardant andpH independent release retardant. Also the use of non-swelling releaseretardants maintains the size of the dosage form thus avoidingvariability of drug release rates arising from variable transit times ofthe dosage form through the gastrointestinal tract.

The term ‘non-swelling’ as used here includes any excipient that doesnot swell in water or swells only moderately. This definition does notinclude excipients such as super disintegrants and polymers such aspolyethylene oxide that swell voluminously in contact with water oraqueous media.

The term ‘release retardant’ as used here means any excipient that canretard the release of an active pharmaceutical ingredient and includespolymers, waxes, fatty acids etc.

A pH dependent release retardant is the one, which has pH dependentsolubility, and hence its performance depends on the pH of theenvironment it encounters.

A pH independent release retardant is the one whose solubility isindependent of pH and hence its performance does not depend on the pH ofthe environment it encounters.

‘Considerable period of time’ as per this invention means the periodequivalent to the normal residence time of the dosage form in thestomach i.e. up to 2-6 hours.

The Active Agent

The present invention provides a sustained release formulation of apharmacologically active agent having an aqueous solubility of greaterthat 1 mg/ml and may be acidic, basic or neutral in character. Theinvention is also applicable to active agents at different dose levelsand variable solubility. The active agents may be selected from one ofthe following therapeutic classes that include:

anti-inflammatory, antipyretic, anticonvulsant and/or analgesic agents,tuberculostats, cardiocirculatory system drugs, antihistaminic agents,hypnotic sedatives, antineoplastic agents, antineoplastic agents,antineoplastic agents, bronchodilators, antiarrhythmic agents, surfaceanesthetics, antiepileptic, synthetic adrenocortical steroids, digestivesystem drugs or antibiotics.

The active agents may be selected from Neomycin Sulphate, Verapamilhydrochloride, Brimonidine tartrate, Morphine Sulphate, Lamivudine,Mepivacaine hydrochloride, Zidovudine, Lisinopril, Ropinirolehydrochloride, Abacavir sulphate, Pentoxifylline, valcyclovirhydrochloride, Albuterol Sulphate, Daunorubicin, Ranitidinehydrochloride, Clonidine hydrochloride, Ondansetron hydrochloride,Diltiazem hydrochloride, Acyclovir Sodium, Albuterol Sulphate,Pravastatin Sodium, Didanosine, Atenolol, Stavudine, Mesalazine Sodium,Zanamirin, Doxycycline hyclate, Donepezil hydrochloride, Methyldopa,Timolol maleate, Naloxone hydrochloride, Alendronate sodium, Rizatriptanbeuzoate, Mecamylamine hydrochloride, Phenoxybenzamine hydrochloride,Captopril, Fluvastatin sodium, Benazepril hydrochloride, AlburerolSulphate, Pentosan polysulphate sodium, Levofloxacin, Cetirizinehydrochloride, Clidaymycin phosphate, Warfarin sodium, Propoxyphenehydrochloride, Potassium chloride, Pramipexole hydrochloride, Metoprololsuccinate, Metoprolol tartrate, Metformin hydrochloride, Losartanpotassium, Methyl phenidate hydrochloride, Montelukast sodium,Bisoprolol fumarate, Oxymorphoine hydrochloride, Amantadinehydrochloride, Sumatriptan succinate, Tramadol hydrochloride,Phenobarbital sodium, Cimetidine hydrochloride, Quinapril hydrochloride,Levomisole hydrochloride, Gabapentin, Ampicillin hydrochloride,Ceftrioxone sodium, Mepiridine hydrochloride, Guanidine hydrochloride,Venlafaxine hydrochloride, Propranolol hydrochloride, Promethazinehydrochloride, Bupropion hydrochloride, Phenylephrine hydrochloride,Ascorbic acid and so on.

In the embodiments of the invention, the active agent can be present inany suitable form. For example, it can be in the form of a particle,powder, a crystal, or a granule.

In certain embodiments of the present invention, one or a combination ofmore than one active ingredients can also be employed.

Amount of active ingredient employed in the dosage form will begenerally dependent on the therapeutically effective amount of theactive ingredient. However the amount of active ingredient present inthe dosage form can range from 1-80%, preferably 5-50% and morepreferably 10-40% by weight of the dosage form

Non-Swelling pH Dependent Release Retardants.

These are the excipients whose performance is dependent on the pH of themedium. A number of such excipients known in the art include polymethacrylic acid derivatives, cellulose derivatives, acrylic acidderivatives, maleic acid copolymers, polyvinyl derivatives etc.

Cellulose based pH dependent release retardant includehydroxypropylmethylcellulose acetate succinate,hydroxypropylmethylcellulose phthalate, hydroxymethylethylcellulosephthalate, cellulose acetate phthalate, cellulose acetate succinate,cellulose acetate maleate, cellulose acetate trimelliate cellulosebenzoate phthalate, cellulose propionate phthalate, methylcellulosephthalate, carboxymethylethylcellulose, ethylhydroxyethylcellulosephthalate and the like.

Acrylic copolymer based pH dependent release retardant includestyrene•acrylic acid copolymer, methyl acrylate acrylic acid copolymer,methyl acrylate•methacrylic acid copolymer, butylacrylate•styrene•acrylic acid copolymer, methacrylic acid•methylmethacrylate copolymer (e.g. Trade-names: Eudragit L 100 and Eudragit S,available from Röhm Pharma), methacrylic acid•ethyl acrylate copolymer(e.g. Trade-name: Eudragit L 100-55, available from Röhm Pharma), methylacrylate•methacrylic acid•octyl acrylate copolymer

Maleic copolymer based pH dependent release retardant includevinylacetate•maleic acid anhydride copolymer, styrene•maleic acidanhydride copolymer, styrene•maleic acid monoester copolymer,vinylmethylether maleic acid anhydride copolymer, ethylene•maleic acidanhydride copolymer, vinylbutylether•maleic acid anhydride copolymer,acrylonitrile methyl acrylate•maleic acid anhydride copolymer, butylacrylate•styrene•maleic acid anhydride copolymer and the like.

Polyvinyl derivative based pH dependent release retardant includespolyvinyl alcohol phthalate, polyvinylacetal phthalate, polyvinylbutylate phthalate, polyvinylacetoacetal phthalate and the like.

Among these examples, methacrylic acid•methylmethacrylate copolymer andmethacrylic acid•ethylacrylate copolymer are preferable which areavailable under the brand name Eudragit®.

Eudragit is the trade name for a number of film coating substances on anacrylic resin basis produced by Rohm Pharma. Eudragit L100® is used inmatrix sustained release formulations especially for reducing burstrelease (excessive drug release in initial hours) by reducing the extentof water penetration in the initial hours as eudragit L100® ishydrophobic in nature and it causes poor wettability of the tabletsurface. However, Eudragit L100® shows pH dependent solubility inaqueous media; insoluble in acidic media but soluble from pH 6.0, whichresults in a pH dependent drug release profile (which means slowerrelease in acidic media and faster release in alkaline media). This pHdependent behavior poses major limitation on the use of Eudragit L100®as sustained release matrix forming agent especially when pH independentdrug release is desired. Examples of other pH dependent polymersbelonging to class of polymethacrylates that can be used in the presentinvention are provided in Table 1.

TABLE 1 pH dependent polymers of polymethacrylates class Generic nameBrand names Marketed by Poly (methacrylic acid, Eudragit L 100 Röhm GmbHmethyl methacrylate) 1:1 Eudragit L 12.5 Röhm GmbH Eudragit L 12.5 PRöhm GmbH Eudragit L 30 D-55 Röhm GmbH Poly (methacrylic acid, EudragitL 100-55 Röhm GmbH ethyl acrylate) 1:1 Eastacryl 30D Eastman ChemicalKollicoat MAE 30 D BASF Fine Chemicals Kollicoat MAE 30 DP BASF FineChemicals Poly (methacrylic acid, Eudragit S 100 Röhm GmbH methylmethacrylate) 1:2 Eudragit S 12.5 Röhm GmbH Eudragit S 12.5 P Röhm GmbH

The pH dependent release retardant may be included in the formulation at10-90% by weight, preferably 15-75% and more preferably 20-50% by weightof the dosage form.

Non-Swelling pH Independent Release Retardants

These are the excipients whose performance is independent of the pH ofthe environment. Many of these are hydrophilic and swell in aqueousenvironment. Such release retardants due to their swelling/gellingnature, may cause variability of drug release and absorption due to foodeffect, adhesion to the mucosa, retention in stomach etc. Therefore inorder to reduce variabilities associated with such swelling excipients,the present invention employs only non-swelling release retardants.

Non-swelling pH independent release retardants may be selected fromexcipients that include polyvinyl alcohol, polyvinyl acetate, KollidonSR (which is a mixture of 8 parts w/w of polyvinyl acetate and 2 partsw/w of polyvinylpyrrolidone, Polymethacrylic acid derivatives, cellulosederivatives such as ethyl cellulose, triglycerides, waxes such ascompritol, lubritab, peceol, gelucires, lipids, fatty acids or theirsalts or derivatives such as stearic acid, etc. Kollidon SR is the mostpreferred release retardant.

Kollidon SR is a sustained release matrix forming agent consisting ofpolyvinyl acetate (8 parts w/w) and polyvinylpyrrolidone (2 parts w/w).It has free-flowing, non-hygroscopic and direct compressibilityproperties (high dry binding capacity). Further, in vitro drug releaseprofiles of tablet formulations with Kollidon SR as sustained releasematrix forming agent are not influenced by the compression force used,pH and ionic strength of the dissolution media, and speed of agitation.This unique property of Kollidon SR makes it one of the most promisingsustained release matrix forming agents especially where pH independentdrug release is desired. However Kollidon SR based formulations havetendency to show higher burst release (excessive drug release in initialhours) by dissolution of drug remaining on the tablet surface as soon asthe tablet comes in contact with aqueous media/fluid. This tendency canlead to deviation of the drug release kinetics far away from theintended zero order kinetics (linear release). Thus, higher burstrelease poses a major limitation to the use of Kollidon SR as sustainedrelease matrix forming agent when initial burst release is to beavoided.

The pH independent release retardant may be included in the formulationat 10-90% by weight concentration, preferably 15-75% and more preferably20-50% by weight

According to a preferred aspect of the present invention, it wassurprisingly found that a combination of a pH dependent releaseretardant (e.g. Eudragit L100®) and a pH independent release retardant(e.g. Kolidon SR) provides pH independent drug release profile alongwith minimal initial burst release of the drug.

The formulation is easy to scale up as it involves processes routinelycarried out in pharmaceutical industry. As the formulation is minimallyaffected by physiological variations, low patient-to-patient variabilityis to be expected.

The controlled release dosage forms according to the present inventioncan be in the form of tablets, capsules, pellets, granules, powders etc.

When the dosage form is in the form of tablets, additional excipientsconventionally known in art such as filler, binders and lubricants maybe incorporated. Fillers such as lactose monohydrate, microcrystallinecellulose, dicalcium phosphate may be used, The binders are selectedfrom the group comprising of starch, polyethylene glycol,polyvinylpyrrolidone, hydroxypropyl methyl cellulose andhydroxypropylcellulose and natural and synthetic gums. Lubricants likeAerosil-200, Magnesium stearate and hydrogenated vegetable oils ortriglycerides of stearic acid, palmitic acid may be utilized.

The said dosage form as per present invention can be prepared by drygranulation or direct compression or wet granulation techniques, usuallyemployed in the industry.

In one of the embodiments of the present invention, the composition mayoptionally be coated. Surface coating may be employed for aestheticpurposes or for dimensionally stabilizing the compressed tablet. Thecoating may be carried out using any conventional technique employingconventional ingredients suitable for enteral use. A surface coating canfor example be in the form of film using conventional polymers such ashydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose, polyvinyl alcohol poly methacrylates and the like.

In another embodiment of the present invention, the composition mayoptionally be coated with a functional coat. The coat can be employedusing hydrophilic polymers, hydrophobic polymers, waxes etc. eitheralone or in combination, along with plasticizers, colorants, opacifiersetc. The functional coat may provide a further reduction in initialburst release to achieve a near zero order drug release profile. Thefunctional coat may also inhibit the release of active ingredient in thestomach, if so desired.

In a further illustrative embodiment, a solid pharmaceutical compositionmay be in the form of a multilayer system for oral administration. Thesystem may be adapted to deliver two different active agents.

In a further illustrative embodiment a solid pharmaceutical compositionin the form of a multilayer system for oral administration is adapted todeliver an active pharmaceutical agent from a first layer immediatelyupon reaching the gastrointestinal tract, and to deliver a furtherpharmaceutical agent which may be same or different from a second layer,in a controlled manner over a specific time period.

While the present invention has been described in terms of its specificembodiments, certain modifications and equivalents will be apparent tothose skilled in the art and are intended to be included within thescope of the present invention.

The details of the invention, its objects and advantages are explainedhereunder in greater detail in relation to non-limiting exemplaryillustrations.

EXAMPLES Example 1 Preparation and the Drug Release Profile of theSustained Release Tablet Dosage Form

This example provides pH independent drug release by formulating amatrix tablet of metoprolol, comprising a pH dependent release from aretarding polymer (Eudragit L100®) and a pH independentrelease-retarding polymer (Kolidon SR).

TABLE 2 Composition of the formulation Composition 1 Ingredients(mg/tablet) Metoprolol succinate 47.5 Poly (methacrylic acid, methyl 80methacrylate) (Eudragit L100 ®) Copovidone (Kollidon VA 64) 10 KolidonSR 70 Magnesium stearate 2.5 Water, Purified q.s.Procedure

Weighed quantities of metoprolol succinate and Eudragit L100® weregranulated using solution of Kollidon VA 64 in water. Granules weremixed with Kolidon SR and magnesium stearate and then compressed on atablet machine.

In vitro drug release was studied in 500 ml of pH 6.8 buffer using USPtype II dissolution apparatus with 50 rpm rotation speed and temperaturebeing 37±1° C.

Table 3 shows the drug release profile of composition 1 in comparisonwith the commercial product of metoprolol succinate tablet dosage form.

TABLE 3 In vitro drug release in pH 6.8 buffer A Marketed productComposition 1 % Cumulative Drug Time (hrs) % Cumulative Drug ReleaseRelease 0 0 0 1 15.5 11.87 2 21.2 14.34 4 33.2 25.43 6 42.3 35.50 8 53.745.75 12 65.4 64.46 16 76.6 77.44 20 84.9 91.5

As evident from the above table and FIG. 1, composition 1 provides arelease profile that is similar to the marketed formulation in pH 6.8medium.

Example 2 pH Independent Release Profile

To determine the pH independent release behavior in vitro dissolution ofcomposition 1 was carried out in 0.1N HCl. The dosage form is expectedto be retained in stomach for a period of 2-4 hours under differentphysiological conditions. Therefore drug release from this dosage formwas studied in 0.1N HCl for a period of 4 hours and the data comparedwith that in pH 6.8 phosphate buffer to prove pH independence.

TABLE 4 In-vitro drug release in different pH media Composition 1Composition 1 (pH 6.8 buffer) (0.1N HCL) Time (hrs) % cum. rel. % cum.rel. 0 0 0 1 15.5 17.2 2 21.2 23.4 4 33.19 30.55

No significant difference in the in vitro release profile was seen inthe two media, indicating that the composition provides a pH independentin vitro drug release profile for a considerable period of time (FIG.2).

Example 3 Preparation and the Drug Release Profile of the SustainedRelease Tablet Dosage Form Comprising Individual Polymers

TABLE 5 Composition of the formulation Composition 2 Composition 3Ingredients (mg/tablet) (mg/tablet) Metoprolol succinate 47.5 47.5 Poly(methacrylic acid, methyl 150 — methacrylate) (EudragitL100 ®)Copovidone (Kollidon VA 64) 10 10 Kolidon SR — 150 Magnesium stearate2.5 2.5 Water, Purified q.s. q.s.Procedure

Weighed quantities of metoprolol succinate and release retardant weregranulated using a solution of Kolidon VA64 in purified water. Thegranules were mixed with balance quantity of release retardant andmagnesium stearate and then compressed using a compression machine.

In vitro drug release was studied in 500 ml of pH 6.8 buffer using USPtype II dissolution apparatus with 50 rpm rotation speed, thetemperature being 37±1° C.

Table 6 shows the drug release profile of both composition 2 and 3

TABLE 6 In vitro drug release in pH 6.8 buffer Composition 2 Composition3 Marketed Product Time % Cumulative Drug % Cumulative Drug CumulativeDrug (hours) Release Release Release 0 0 0 0 1 21.2 18.1 11.9 2 39.833.8 14.3 4 66.2 59.3 25.4 6 84.6 76.1 35.5 8 97.5 87.9 45.8

It is evident from the above examples and FIG. 3, that when both releaseretardants were employed alone, the resulting release profile was muchfaster than the marketed product as well as than the product having acombination of the two release retarding polymers (Composition 1).

Aforesaid results clearly establish the synergy existing in thecombination of a non-swelling pH dependent release retarding polymer anda non-swelling pH independent release-retarding polymer.

Example 4 Preparation and the Drug Release Profile of the SustainedRelease Tablet Dosage Form Coated with a Functional Coat

TABLE 7 Composition of the formulation Composition 4 Ingredients(mg/tablet) Metoprolol succinate 190 Poly (methacrylic acid, methyl 160methacrylate) (Eudragit L100 ®) Copovidone (Kollidon VA 64) 50 KollidonSR 140 Magnesium stearate 10 Hypromellose 5 cps 44 Ethyl celluloseaqueous dispersion 11 Glycerin 4.4 Water, Purified q.s.Procedure

Weighed quantities of metoprolol succinate and Eudragit L100® weregranulated using a solution of Kollidon VA 64 in water. The granuleswere mixed with Kollidon SR, Kollidon VA64 and magnesium stearate andthen compressed. The tablets were further coated with a functional coatof ethyl cellulose and hypromellose.

In vitro drug release was studied in pH 6.8 buffer and pH changedissolution media (i.e. 0.01N HCl for 2 hrs followed by pH 6.8 bufferfor 18 hrs) using USP type II dissolution apparatus with 50 rpm rotationspeed temperature being 37±1° C.

Table 8 shows the drug release profile of composition 4 in pH 6.8 bufferand pH change media.

TABLE 8 In vitro drug release in pH 6.8 buffer and pH change media Time% Cumulative Drug Release in % Cumulative Drug Release (hours) pH 6.8buffer in pH change media 0 0 0 1 4.3 6.1 2 10.7 10.9 4 23.9 25.7 8 48.456.4 12 69.1 77.5 20 97.2 96.2

As evident from above table and FIG. 4, a pH independent release profileis achieved with composition 4.

Example 5 Preparation and the Drug Release Profile of the SustainedRelease Tablet Dosage Form

TABLE 9 Composition of the formulation Composition 5 Ingredients(mg/tablet) Metformin HC1 500 Poly (methacrylic acid, methyl 200methacrylate) (Eudragit L100 ®) Copovidone (Kollidon VA 64) 16 KolidonSR 400 Microcrystalline cellulose 72 Magnesium stearate 12 Water,Purified q.s.Procedure

Weighed quantities of metformin HCl and Eudragit L100® were granulatedusing solution of Kolidon VA64 in purified water. Granules were andmixed with Kolidon SR and Avicel PH 102. The blend was lubricated usingmagnesium stearate. The lubricated blend was compressed using capsuleshaped punches.

In vitro drug release was studied in 900 ml pH 6.8 buffer using USP typeI dissolution apparatus with 100 rpm rotation speed temperature being37±1° C.

Table 10 shows the drug release profile of composition 5 in comparisonwith the commercial metformin HCl extended release tablet dosage form.

TABLE 10 In vitro drug release in pH 6.8 buffer Marketed Composition 5Formulation % Cumulative Drug % Cumulative Drug Time (hours) ReleaseRelease 0 0 0 1 34.2 25.9 2 47.0 39.6 4 63.4 57.9 6 75.8 70.2 8 83.078.6 12 90.4 90.3

As evident from above table and FIG. 5, composition 5 provides a drugrelease profile that is similar to that of the marketed formulation inpH 6.8 medium.

Example 6 Preparation and In Vitro Release Profile of Ascorbic AcidSustained Release Tablet

TABLE 11 Composition of the formulation Composition 6 Ingredients(mg/tablet) Ascorbic acid 500 Poly (methacrylic acid, methyl 250methacrylate) (Eudragit L100 ®) Copovidone (Kollidon VA 64) 40 KollidonSR 200 Magnesium stearate 10 Water, Purified q.s.Procedure

Weighed quantities of ascorbic acid, Eudragit L1000 and a part ofKollidon SR were granulated using solution of Kolidon VA64 in purifiedwater. The granules were dried mixed with remaining quantity of KolidonSR and Kollidon VA 64 and lubricated using magnesium stearate. Thelubricated blend was compressed using oval punches. In vitro drugrelease was studied in 900 ml pH 6.8 buffer using USP type I dissolutionapparatus with 100 rpm rotation speed temperature being 37±1° C.

Table 12 shows the drug release profile of composition 7 in pH 6.8buffer.

TABLE 12 In vitro drug release in pH 6.8 buffer Composition 6 %Cumulative Drug Time (hours) Release 0 0 1 46.9 2 61.2 4 81.6 6 93.4 8100.7

As evident from above table, it can be concluded that a combination ofnon swelling pH independent and non swelling pH dependent polymer canretard release of a high dose highly soluble drug ascorbic acid.

Example 7 Preparation of Phenylephrine Hydrochloride Sustained ReleaseTablet

TABLE 13 Composition of the formulation Composition 7 Ingredients(mg/tablet) Phenylephrine hydrochloride 30 Poly (methacrylic acid,methyl 15 methacrylate) (Eudragit L100 ®) MCC Avicel PH 102 93 KollidonSR 60 Magnesium stearate 2Procedure

Weighed quantities of phenylephrine hydrochloride, Eudragit L100, MCCAvicel PH 102, Kollidon SR and Magnesium stearate were mixed in ablender and then compressed into tablets.

The tablets of phenylephrine hydrochloride obtained showed good hardnessand low friability.

Example 8 Preparation of Venlafaxine Hydrochloride Sustained ReleaseTablet

TABLE 14 Composition of the formulation Composition 8 Ingredients(mg/tablet) Venlafaxine hydrochloride 84.86 (equivalent to 75 mgVenlafaxine base) Hydroxy propylmethyl phthalate 150.0 Kollidon SR 100.0Microcrystalline cellulose 38.14 Povidone QKollidon K30) 20.0 Magnesiumstearate 8.0 Water, Purified q.s.Procedure

Weighed quantities of Venlafaxine hydrochloride, Hydroxy propylmethylphthalate, and Microcrystalline cellulose were mixed in a blender. Theblend was granulated using solution of povidone in water. Granules weredried, sifted and lubricated using Kollidon SR and Magnesium stearateand compressed.

The tablets of venlafexine hydrochloride obtained showed good hardnessand low friability.

Example 9 Preparation of Propranolol Hydrochloride Sustained ReleaseTablet

TABLE 15 Composition of the formulation Composition 9 Ingredients(mg/tablet) Propranolol hydrochloride 120.0 Eudragit S 50.0 Kollidon SR350.0 Dicalcium phosphate 70.0 Starch 1500 30.0 Aerosil 6.0 Talc 6.0Water, Purified q.s.Procedure

Weighed quantities of Propranolol hydrochloride, Eudragit S, KollidonSR, Dicalcium phosphate and Starch 1500 were mixed in a blender. Themass was granulated using water, dried, sifted and lubricated usingAerosil and Talc and finally compressed into tablets.

The tablets of Propranolol hydrochloride exhibited desired performancecharacteristics.

Example 10 Preparation of Bupropion Hydrochloride Sustained ReleaseTablet

TABLE 16 Composition of the formulation Composition 10 Ingredients(mg/tablet) Bupropion hydrochloride 150.0 Eudragit L-100 150.0 Compritol150.0 Lactose 75.0 Magnesium stearate 5.0Procedure

Weighed quantities of Bupropion hydrochloride and Eudragit S were mixedin a blender. The mass was granulated using molten compritol. Granulesof Bupropion thus obtained were further blended using Kollidon SR andlactose, lubricated using magnesium stearate and compressed intotablets.

The tablets of Bupropion hydrochloride exhibited desired physical andchemical characteristics.

Example 11 Preparation of Tramadol Hydrochloride Sustained ReleaseTablet

TABLE 17 Composition of the formulation Composition 11 Ingredients(mg/tablet) Tramadol hydrochloride 200.0 Hydroxy propylmethyl phthalate200.0 Eudragit RS-PO 150.0 Silicifled microcrystalline cellulose 150.0Kollidon VA64 35.0 Magnesium stearate 8.0 Water, Purified q.s.Procedure

Weighed quantities of Tramadol hydrochloride, Hydroxy propylmethylphthalate, Eudragit RS-PO and Silicified microcrystalline cellulose weremixed in a blender. The blend was then granulated using a solution ofKollidon VA64 in water. Granules were dried, sifted and lubricated usingMagnesium stearate and compressed.

The tablets of Tramadol hydrochloride obtained showed good hardness andlow friability.

Example 12 Preparation of Methylphenidate Sustained Release Tablet

TABLE 18 Composition of the formulation Composition 12 Ingredients(mg/tablet) Methylphenidate hydrochloride 20.0 Eudragit L100 50.0Lubritab 100.0 Microcrystalline cellulose 25.0 Magnesium stearate 2.0Aerosil 3.0Procedure

Weighed quantities of methylphenidate hydrochloride, Eudragit L100,microcrystalline cellulose and Lubritab were mixed in a blender. Themass was heated to about 50° C. to carry out melt granulation. Mass wascooled and the resulting granules were lubricated using magnesiumstearate and compressed into tablets.

The tablets of methylphenidate hydrochloride obtained, showed desiredphysical and chemical characteristics were obtained.

Example 13 Preparation of Ropinirole Hydrochloride Sustained ReleaseTablet

TABLE 19 Composition of the formulation Composition 13 Ingredients(mg/tablet) Ropinirole hydrochloride 3.42 (equivalent to 3.0 mg base)Eudragit L100 15.0 Kollidon SR 85.0 Microcrystalline cellulose 18.58Aerosil 2.0 Magnesium stearate 1.0Procedure

Weighed quantities of ropinirole hydrochloride, Eudragit L100,microcrystalline cellulose, Kollidon SR and Magnesium stearate weremixed in a blender and then compressed into tablets.

The tablets of ropinirole hydrochloride obtained showed good hardnessand low friability.

Example 14 Preparation of Verapamil Hydrochloride Sustained ReleaseTablet

TABLE 20 Composition of the formulation Composition 14 Ingredients(mg/tablet) Verapamil hydrochloride 240.0 Eudragit L100 75.0 Compritol75.0 Kollidon SR 320.0 Lactose 40.0 Aerosil 12.0 Magnesium stearate 6.0Procedure

Weighed quantities of verapamil hydrochloride and Eudragit L100 weremixed in a blender. The mass was granulated using molten compritol.Granules of verapamil thus obtained were further blended using KollidonSR and lactose, lubricated using magnesium stearate and compressed intotablets.

The tablets of verapamil hydrochloride obtained exhibited desiredphysical and chemical characteristics.

The invention claimed is:
 1. A sustained release oral dosage formcomprising: (a) a therapeutically effective amount of at least onepharmacologically active ingredient having aqueous solubility of greaterthan 1 mg/ml, (b) at least one non-swelling pH dependent releaseretardant, and (c) at least one non-swelling pH independentrelease-retardant; wherein the dosage form provides pH independent drugrelease for a considerable period of time after administration, and thedosage form is a matrix type dosage form.
 2. The sustained release oraldosage form of claim 1, wherein said pharmacologically active ingredientis selected from class of anti-inflammatory, antipyretic, anticonvulsantand/or analgesic agents, tuberculostats, cardiocirculatory system drugs,antihistaminic agents, hypnotic sedatives, antineoplastic agents,bronchodilators, antiarrhythmic agents, surface anesthetics,antiepileptic, synthetic adrenocortical steroids, digestive systemdrugs, antibiotics, or combinations thereof.
 3. The sustained releaseoral dosage form of claim 1, wherein said pharmacological activeingredient is selected from Neomycin Sulphate, Verapamil hydrochloride,Brimonidine tartrate, Morphine Sulphate, Lamivudine, Mepivacainehydrochloride, Zidovudine, Lisinopril, Ropinirole hydrochloride,Abacavir sulphate, Pentoxifylline, valcyclovir hydrochloride,Daunorubicin, Ranitidine hydrochloride, Clonidine hydrochloride,Ondansetron hydrochloride, Diltiazem hydrochloride, Acyclovir Sodium,Albuterol Sulphate, Pravastatin Sodium, Didanosine, Atenolol, Stavudine,Mesalazine Sodium, Zanamirin, Doxycycline hyclate, Donepezilhydrochloride, Methyldopa, Timolol maleate, Naproxen, Naloxonehydrochloride, Alendronate sodium, Rizatriptan benzoate, Mecamylaminehydrochloride, Phenoxybenzamine hydrochloride, Captopril, Fluvastatinsodium, Benazepril hydrochloride, Pentosan polysulphate sodium,Levofloxacin, Cetirizine hydrochloride, Clidaymycin phosphate, Warfarinsodium, Propoxyphene hydrochloride, Potassium chloride, Pramipexolehydrochloride, Metoprolol succinate, Metoprolol tartrate, Metforminhydrochloride, Losartan potassium, Methyl phenidate hydrochloride,Montelukast sodium, Bisoprolol fumarate, Oxymorphoine hydrochloride,Amantadine hydrochloride, Sumatriptan succinate, Tramadol hydrochloride,Phenobarbital sodium, Cimetidine hydrochloride, Quinapril hydrochloride,Levomisole hydrochloride, Gabapentin, Ampicillin hydrochloride,Ceftrioxone sodium, Mepiridine hydrochloride, Guanidine hydrochloride,Venlafaxine hydrochloride, Propranolol hydrochloride, Promethazinehydrochloride, Bupropion hydrochloride, phenylephrine hydrochloride,ascorbic acid or combinations thereof.
 4. The sustained release oraldosage form of claim 1, wherein said non-swelling pH dependent releaseretardant is selected from polymethacrylic acid derivatives, cellulosederivatives, acrylic acid derivatives, maleic acid copolymers, polyvinylderivatives or mixtures thereof.
 5. The sustained release oral dosageform of claim 1, wherein said non-swelling pH dependent releaseretardant is present in an amount from about 10 to about 90% by weightof the total composition.
 6. The sustained release oral dosage form ofclaim 1, wherein said non-swelling pH independent, release retardant isselected from polyvinyl alcohol, polyvinyl acetate, a mixture ofpolyvinyl acetate (8 parts w/w) and polyvinylpyrrolidone (2 parts w/w),polymethacrylic acid derivatives, cellulose derivatives, waxes, lipids,fatty acids, fatty acid derivatives or combinations thereof.
 7. Thesustained release oral dosage form of claim 1, wherein said non-swellingpH independent release retardant is present in an amount from about 10to about 90% by weight of the total composition.
 8. The sustainedrelease oral dosage form of claim 1 further comprising binder,lubricant, or diluent.
 9. The sustained release dosage form of claim 1,wherein said dosage form is a tablet, capsule, pellet, granule, orpowder.
 10. The sustained release oral dosage form of claim 9, whereinsaid dosage form is prepared by wet granulation, direct compression, drygranulation or molding method.
 11. The sustained release oral dosageform of claim 1, wherein said dosage form is coated.
 12. The sustainedrelease oral dosage form of claim 11, wherein said coated tabletcomprises coat in the form of quick dissolving film of polymer selectedfrom the group of hydroxypropylmethyl cellulose, hydroxypropylcellulose, carboxymethyl cellulose, polyvinyl alcohol, poly methacrylateor mixtures thereof.
 13. The sustained release oral dosage form of claim11, wherein said coat is functional coat.
 14. The sustained release oraldosage form of claim 13, wherein said functional coat comprises polymerselected from the group consisting of hydrophilic polymers, hydrophobicpolymers, waxes or mixtures thereof.
 15. The sustained release oraldosage form of claim 1, wherein said dosage form is multilayered tablet.16. A method of administering a pharmaceutically active ingredienthaving aqueous solubility of greater than 1 mg/ml, the method comprisingorally administering a sustained release oral dosage form comprising:(a) a therapeutically effective amount of at least one pharmacologicallyactive ingredient having aqueous solubility of greater than 1 mg/ml, (b)at least one non-swelling pH dependent release retardant, and (c) atleast one non-swelling pH independent, release-retardant; wherein thedosage form provides pH independent drug release for a considerableperiod of time after administration and the dosage form is a matrix typedosage form.
 17. The sustained-release oral dosage form of claim 16,wherein said non-swelling pH dependent release retardant is present inan amount from about 10 to about 90% by weight of the total compositionand said non-swelling pH independent release retardant is present in anamount from about 10 to about 90% by weight of the total composition.18. The sustained release oral dosage form of claim 5, wherein saidnon-swelling pH independent release retardant is present in an amountfrom about 15% to about 75% by weight of the total composition.
 19. Thesustained release oral dosage form of claim 7, wherein said non-swellingpH dependent release retardant is present in an amount from about 15% toabout 75% by weight of the total composition.
 20. A sustained-releaseoral dosage form comprising, (a) a therapeutically effective amount ofpharmacologically active ingredient having solubility of greater than 1mg/ml, (b) non-swelling pH-dependent release retardant, and (c) ethylcellulose; wherein the dosage form provides a pH independent drugrelease for a considerable period of time after administration and thedosage form is a matrix type dosage form.